Despite progress in efficacious treatments for individuals with autism spectrum disorder (ASD), few interventions are available for disease-specific impairments. The complexity and heterogeneity of ASD suggests interventions targeting multiple domains are more likely to have a therapeutic impact. This Mentored Patient-Oriented Research Career Development Award supports the candidate's long-term goals of building effective interventions for core symptoms in ASD with capacity to integrate the rapidly evolving findings from both behavioral intervention and drug discovery research. The training program and supervised activities will focus on gaining expertise in the molecular and neural mechanisms underlying phenotypic diversity in ASD, interrogating active ingredients from combination therapies, and investigating mechanisms underlying both behavioral and pharmacological treatments. The award is will be based at the Rush University Medical Center under the mentorship of Dr. Mark Pollack and co-mentorship of Drs. Ed Cook, Luan Phan, and Don Hedeker at the University of Illinois-Chicago; and with consultation from national experts including Drs. Connie Kasari (University of California, Los Angeles), Linmarie Sikich (University of North Carolina-Chapel Hill), and Kevin Pelphrey (Yale School of Medicine). The candidate's immediate focus is to study a novel, behavioral- pharmacological therapy targeting higher-order social information processing impairments in youth with ASD. The research plan proposes a proof-of-concept, combination intervention designed to address individual treatment targets presumed to influence social learning in school aged children with ASD. This proposal builds upon data from the applicant's randomized, comparative trial of a targeted cognitive-behavioral intervention (CBI) for nonverbal communication, emotion recognition, and theory of mind deficits in youth with ASD. We will evaluate the safety, tolerability, and efficacy of combining the neuropeptide oxytocin (OT) with the targeted CBI group curriculum. The research plan will randomize 8-11 year old youth with ASDs (n=50), into a 12- session, randomized, parallel group design of CBI+OT or a control social group condition (facilitated play). It is hypothesized that targeted, intranasal OT dosing immediately prior to CBI group activities will serve enhance social cognition during group and homework activities, facilitate behavioral rehearsal of target skills, and yield changes in both behavioral and cognitive domains supporting social learning during childhood. In collaboration with the mentorship team, the research plan will investigate a candidate task battery drawing from neuroscience measurement strategies of brain-behavior relationships underlying social cognition and affective regulation. The candidate task battery will be used refine treatment targets and identify potential social cognitive mechanisms predicting treatment response from the combined social cognitive intervention.